Hypertensive left ventricular hypertrophy is recognized to be the most common clinical precursor of congestive heart failure. A decreased contractile responsiveness to adrenergic stimulation of the hypertrophied but compensated heart has been identified in previous investigations of the Spontaneously Hypertensive Rat (SHR) and has been proposed to be a mechanism by which the heart in hypertension ultimately decompensates to a state of congestive failure. The objective of this research proposal is to examine the role of endogenous myocardial adenosine in the mediation of dysfunctional inotropic responses to cardiac beta- adrenoreceptor stimulation in chronic anti-adrenergic effect by which it negatively modulates catecholamine-induced positive inotropic effects in the normal nonhypertrophied heart. The working hypothesis of this proposal is that elevated levels of cardiac adenosine are responsible for the attenuated catecholamine-elicited cardiac contractile responses which prevail during the nonfailing stage of hypertensive left ventricular hypertrophy in the SHR. Utilizing the isolated perfused heart preparation the specificity of inotropic dysfunction in this model of hypertension will be characterized by determining the mechanical response of the hypertrophied heart to both catecholamine and noncatecholamine mediators. Experimental determinations will be made of coronary effluent adenosine release rates as well as interstitial myocardial adenosine concentrations in the basal and beta-adrenergically stimulated SHR heart. The influence of normotensive perfusion pressure upon the aerobic metabolism and adenosine production of the hypertrophied heart will be evaluated. The results of the proposed investigation will potentially provide novel insights into the biochemical regulation of the inotropic function of the hypertrophied heart in arterial hypertension and thereby enhance our understanding of the process of the cardiac mechanical decompensation in this disease. Such insights can provide a rational basis for the refinement of clinical therapeutic strategies and the design of new pharmacologic agents.